Project Summary: Stoichiometric palladium has been found to be capable of mediating the dearomatization of an aromatic precursor to form spirocyclic dienones. There was seen a potential for this reaction to be used in the synthesis of Amaryllidaceae alkaloids that are characterized by a unique spirocyclic framework containing a chiral quaternary carbon. The total syntheses proposed herein would utilize a catalytic version of this method. The syntheses are simple, straightforward and rely on inexpensive starting materials. The proposed methodology presents an advantage over current methods, because it is economical and likely capable of proceeding in an asymmetric fashion if chiral ligands on palladium are used. Cationic palladium centers in complexes containing bulky, chiral, monodentate ligands are proposed to be electrophilic enough to coordinate to an aromatic ring and thus activate it towards dearomatization. Specifically, this proposal aims to (1) develop an asymmetric palladium-catalyzed spirocycle forming dearomatization reaction and (2) utilize the method in the total synthesis of cytotoxic alkaloids of the Amaryllidaceae family. First, catalytic palladium conditions will be optimized for use with simple model substrates. Once catalytic conditions have been established, the reaction will be tested on a number of other related substrates in order to broaden the scope of the reaction. Finally, the natural product precursors will be prepared and the methodology applied to the synthesis of four Amaryllidaceae alkaloids. Relevance: Cancer treatment and drug development rely on a steady source of drug candidates and material for testing against cancer cells. Inspiration for drug treatment by Pharmaceuticals comes from the structures of naturally occurring cytotoxic compounds, but their availability through standard isolation methods is often limited. These studies will contribute to our ability to synthesize potential cancer therapeutics that contain a spirocyclic framework. The methodology may also be extended to the synthesis of other structurally related chemotherapeutic agents in addition to the targeted alkaloids.